Derivatives of biphenyl alkyl carboxylates and their use as medicaments

ABSTRACT

This invention relates to new derivatives of biphenyl alkyl carboxylates, to a process for the preparation thereof and the use thereof as medicaments. 
     The new derivatives according to the present invention correspond to general formula (I): ##STR1## wherein X represents a hydrogen atom or a halogen atom, 
     R represents a hydrogen atom or an alkyl group, and 
     R 1  represents the following groups: ##STR2## These compounds will notably be used in the treatment of obstinate pains and inflammatory syndromes.

BACKGROUND OF THE INVENTION

This invention relates to new derivatives of biphenyl acetic acid, aprocess for the preparation thereof and the use thereof in therapeutics.

These new active principles have anti-inflammatory and pain-killingproperties and are notably useful as medicaments for the treatment ofvarious pains and types of rheumatism.

The invention also relates to pharmaceutical compositions containingthese new compounds and the therapeutically acceptable salts thereof.

SUMMARY OF THE INVENTION

The compounds which are an object of the present invention correspond tothe general formula (I): ##STR3## wherein

X represents a hydrogen atom or a halogen atom,

R represents a hydrogen atom or an alkyl group, and

R₁ represents the following groups: ##STR4## wherein

X₁ represents a hydrogen atom or a halogen atom or a CF₃ radical, and

Y represents an alkyl group or an aryl group optionally substituted by ahalogen atom or by a CF₃ radical.

DETAILED DESCRIPTION

The term "alkyl" as used herein designates a linear or branchedhydrocarbon radical containing from 1 to 4 carbon atoms.

The therapeutically acceptable salts of the compounds corresponding tothe general formula (I) are mainly addition salts or salts of mineral ororganic acids, such as hydrochloric acid, phosphoric acid, sulphuricacid, maleic acid, succinic acid, fumaric acid and citric acid etc.

The new derivatives of biphenyl acetic acid corresponding to the generalformula (I) according to the present invention may be obtained, forexample, by treating an acid corresponding to general formula (II):##STR5## with a chloroacetylated derivative corresponding to generalformula (III): ##STR6## in the presence of an alkaline carbonate and acatalyst, such as potassium iodide.

Some non-limiting Examples of the preparation of derivativescorresponding to the general formula (I) according to the presentinvention will be provided in the following simply by way ofillustration.

EXAMPLE 1 Preparation of N-phenyl parabiphenylacetoxyacetamide

11 grammes (80 mmoles) of potassium carbonate are ground in the presenceof 300 mg of potassium iodide. This mixture is added to 16.34 g (77mmoles) of p-biphenylacetic acid in suspension in a solution of 11.9 g(70 mmoles) of chloroacetanilide in 200 ml of methylethylketone.

The reaction mixture is brought to reflux for 5 hours. After returningto ambient temperature, the mixture is poured into cold water. Theorganic phase is washed with an aqueous solution of sodium carbonate,then with water until neutral. It is dried over sodium sulphate in thepresence of animal charcoal, and the insoluble matter is then removed byfiltration. The solvent is evaporated under reduced pressure. Theresulting crystals are recrystallised in a methylethylketone-hexanemixture (30/70). 73% of product corresponding to the following formulaare recovered after filtration and drying: ##STR7##

Empirical formula: C₂₂ H₁₉ NO₃

Molecular weight: 345.4

Crystals: white

Melting point: 133° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:ethyl acetate-petroleum ether 30/70, detection: UV and iodine, Rf: 0.35.

Infrared spectrum (KBr pellet): νC=O (ester) 1750 cm⁻¹ ; νC=O (amide)1660 cm⁻¹.

NMR spectrum (DMSO d₆): δppm: 3.85 (s, 2H, CH₂ --COO); 4.75 (s, 2H,##STR8## 7-7.8 (m, 14H aromatic); 10.05 (s, 1H,N--H)

EXAMPLE 2 Preparation ofN(metatrifluoromethylphenyl)parabiphenylacetoxyacetamide

55% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but usingmetatrifluoromethyl chloroacetanilide: ##STR9##

Empirical formula: C₂₃ H₁₈ F₃ NO₃

Molecular weight: 413.4

Crystals: white

Melting point: 90° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:ethyl acetate-petroleum ether 30/70, detection: UV and iodine, Rf: 0.35.

Infrared spectrum (KBr): νC=O (ester) 1740 cm⁻¹ ; νC=O (amide) 1670cm⁻¹.

NMR spectrum (DMSO d₆): δppm: 3.9 (s, 2H, CH₂ --CO₂); 4.75 (s, 2H,##STR10## 7.2-7.8 (m, 13H aromatic); 10.4 (s, 1H, NH).

EXAMPLE 3 Preparation of 4-methyl-1-parabiphenylacetoxyacetyl piperazinehydrochloride

60% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but using4-methyl-1-chloroacetyl piperazine: ##STR11##

Empirical formula: C₂₁ H₂₅ ClN₂ O₃

Molecular weight: 388.9

Crystals: white

Melting point: 174°-176° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:chloroform-methanol 90/10, detection: UV and iodine, Rf: 0.5.

Infrared spectrum (KBr): νC=O (ester) 1745 cm⁻¹ ; νC=O (amide) 1670cm⁻¹.

EXAMPLE 4 Preparation of 4-phenyl-1-parabiphenylacetoxyacetyl piperidine

65% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but using4-phenyl-1-chloroacetyl piperidine: ##STR12##

Empirical formula: C₂₇ H₂₇ NO₃

Molecular weight: 413.5

Crystals: white

Melting point: 93° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:ethyl acetate-petroleum ether 50/50, detection: UV and iodine, Rf: 0.45.

Infrared spectrum (KBr): νC=O (ester) 1750 cm⁻¹ ; νC=O (amide) 1660cm⁻¹.

EXAMPLE 5 Preparation of4-(metatrifluoromethylphenyl)-1-parabiphenylacetoxyacetyl piperazinehydrochloride

70% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but using4-(metatrifluoromethylphenyl)-1-chloroacetyl piperazine and hydrochloricacid as a salt-forming agent: ##STR13##

Empirical formula: C₂₇ H₂₆ ClF₃ N₂ O₃

Molecular weight: 518.9

Crystals: white

Melting point: slow decomposition between 100° and 110° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:ethyl acetate-petroleum ether, detection: UV and iodine, Rf: 0.40.

Infrared spectrum (KBr): νC=O (ester) 1750 cm⁻¹ and νC=O (amide) 1670cm⁻¹.

EXAMPLE 6 Preparation of 4-phenyl-1-[(4-phenyl phenyl)acetoxyacetyl]piperazine:

71% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but using4-phenyl-1-chloroacetyl piperazine: ##STR14##

Empirical formula: C₂₆ H₂₆ N₂ O₃

Molecular weight: 414.5

Crystals: white

Melting point: 92° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:ethyl acetate-petroleum ether 30/70, detection: UV and iodine, Rf: 0.65.

Infrared spectrum (KBr): νC=O (ester) 1740 cm⁻¹ and νC=O (amide) 1650cm⁻¹.

NMR spectrum (DMSO d₆): δppm: 2.9-3.2 (m, 4H, Ph--N--CH₂); 3.2-3.7 (m,4H, ##STR15## 3.8 (s, 2H, Ph--CH₂ --CO); 4.7 (s, 2H, O--CH₂ --C═O );6.8-7.7 (m, 14H aromatic).

EXAMPLE 7 Preparation of 4-methyl-1-[(4-orthochlorophenyl phenyl)acetoxyacetyl] piperazine hydrochloride

83% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but usingorthochlorobiphenyl acetic acid and chloroacetyl piperazine, thenforming a salt with hydrochloric acid: ##STR16##

Empirical formula: C₂₁ H₂₄ Cl₂ N₂ O₃

Molecular weight: 423.3

Crystals: white

Melting point: slow decomposition from 190° to 200° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:chloroform-methanol 90/10, detection: UV and iodine,

Rf: 0.55.

Infrared spectrum (KBr): νC=O (ester) 1750 cm⁻¹ and νC=O (amide) 1670cm⁻¹.

EXAMPLE 8 4-phenyl-1-[(4-orthochlorophenyl)phenyl-acetoxyacetyl]piperazine hydrochloride

67% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but usingorthochlorobiphenyl acetic acid, and 4-phenyl chloroacetyl piperazine,then forming a salt with hydrochloric acid: ##STR17##

Empirical formula: C₂₆ H₂₆ Cl₂ N₂ O₃

Molecular weight: 485.4

Crystals: white

Melting point: 136°-140° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:chloroform-methanol 95/5, detection: UV and iodine, RF: 0.55.

Infrared spectrum (KBr): νC=O (ester) 1750 cm⁻¹ and νC=O (amide) 1670cm⁻¹.

EXAMPLE 9 Preparation of4-metatrifluoromethylphenyl-1-[4-(orthochlorophenyl)phenylacetoxyacetyl] piperazine hydrochloride

62% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but usingorthochlorobiphenyl acetic acid and 4-phenyl chloroacetyl piperazine,then forming a salt with hydrochloric acid: ##STR18##

Empirical formula: C₂₇ H₂₅ Cl₂ N₂ O₃ F₃

Molecular weight: 553.4

Crystals: white

Melting point: 134° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:chloroform-methanol 95/5, detection: UV and iodine, Rf: 0.61.

Infrared spectrum (KBr): νC=O (ester) 1755 cm⁻¹ and νC=O (amide) 1670cm⁻¹.

EXAMPLE 10 Preparation of 4-(metachlorophenyl)-1-[(4-orthochlorophenylphenyl)acetoxyacetyl] piperazine hydrochloride

73% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but usingorthochlorobiphenyl acetic acid and 1-chloroacetyl-4-metachlorophenylpiperazine, then forming a salt with hydrochloric acid: ##STR19##

Empirical formula: C₂₆ H₂₅ Cl₃ N₂ O₃

Molecular weight: 519.8

Crystals: white

Melting point: 128° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:chloroform-metahnol 95/5, detection: UV and iodine, Rf: 0.60.

Infrared spectrum (KBr): νC=O (ester) 1750 cm⁻¹ and νC=O (amide) 1660cm⁻¹.

EXAMPLE 11 Preparation of [2-(4-phenyl 1-piperazinyl)-2-oxo] ethyl2-parabiphenyl propionate

50% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but using2-para-biphenylyl proprionic acid and N'-phenyl-N-chloroacetylpiperazine: ##STR20##

Empirical formula: C₂₇ H₂₈ N₂ O₂

Molecular weight: 428.5

Crystals: white

Melting point: 92° C.

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:toluene/ethyl acetate 70/30, detection: UV and iodine, Rf: 0.38.

Infrared spectrum (KBr): νC=O (ester) 1740 cm⁻¹ and νC=O (amide) 1660cm⁻¹.

EXAMPLE 12 Preparation of 2-(4-methylpiperazino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate hydrochloride

62% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but using2-(4-orthochlorophenyl phenyl) propionic acid and4-methyl-1-chloroacetyl piperazine, then forming a salt withhydrochloric acid: ##STR21##

Empirical formula: C₂₂ H₂₆ Cl₂ N₂ O₃

Molecular weight: 437.3

Crystals: white

Melting point: 210° C. (instantaneous)

Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent:chloroform-methanol 90/10, detection: UV and iodine, Rf: 0.51.

Infrared spectrum (KBr): νC=O (ester) 1745 cm⁻¹ and νC=O (amide) 1675cm⁻¹.

NMR spectrum (DMSO d₆): δppm: 1.45 (d, 3H,CH₃ --C); 2.7 (s, 3H,CH₃ --N);2.8-4.2 (m, 10H, (CH₂)₄, exchangeable, CH--CH₃); 4.85 (s, 2H, O--CH₂--CO); 7.35 (s,8H aromatic).

EXAMPLE 13 Preparation of 2-(4-phenylpiperazino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate

82% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but using2-(4-orthochlorophenyl phenyl)propionic acid and 1-phenyl chloroacetylpiperazine: ##STR22##

Empirical formula: C₂₇ H₂₇ ClN₂ O₃

Molecular weight: 462.9

Crystals: light beige

Melting point: 114° C.

Plate chromatography: support: silica gel 60 G 254 Merck®, solvent:chloroform-methanol 99/1, detection: UV and iodine, Rf: 0.51.

Infrared spectrum (KBr): νC=O (ester) 1745 cm⁻¹ and νC=O (amide) 1650cm⁻¹.

NMR spectrum (DMSO d₆): δppm: 2.95 (d,3H,CH₃ --C); 2.8-3.6 (m,8H,CH₂piperazine); 3.6-4.2 (q,1H,CH₃ --CH); 4.8 (s,2H, O--CH₂ --C═O); 6.6-7.5(m,13H aromatic).

EXAMPLE 14 Preparation of 2-(4-phenylpiperidino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate

75% of product corresponding to the following formula are obtained by amethod similar to the one described in Example 1, but using2-(4-orthochlorophenyl phenyl)propionic acid and 4-phenyl-1-chloroacetylpiperidine: ##STR23##

Empirical formula: C₂₈ H₂₈ ClNO₃

Molecular weight: 461.9

Crystals: white

Melting point: 74° C.

Plate chromatography: support: silica gel 60 F 254 Merck®, solvent:chloroform-methanol 99/1, detection: UV and iodine, Rf: 0.35.

Infrared spectrum (KBr): νC=O (ester) 1740 cm⁻¹ and νC=O (amide) 1650cm⁻¹.

EXAMPLE 15 Preparation of 2-(2-aminopyridine)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate oxalate

A product corresponding to the following formula is obtained by a methodsimilar to the one described in Example 1, but using2-(4-orthochlorophenyl phenyl)propionic acid and 2-chloroacetylaminopyridine: ##STR24##

Empirical formula: C₂₄ H₂₁ ClN₂ O₇

Molecular weight: 484.89

Crystals: light beige

Melting point: instantaneous 160° C.

Plate chromatography: support: silica gel 60 F 254 Merck®, solvent:chloroform-acetone 90/10, detection: UV and iodine, Rf: 0.81

Infrared spectrum (KBr): νC=O (ester) 1735 cm⁻¹ and νC=O (amide) 1630cm⁻¹.

EXPERIMENTS

The above-described derivatives were the subject of pharmacological andtoxicological experiments which have made it possible to demonstrateadvantageous pain-killing and anti-inflammatory properties.

(A) Toxicology

A toxicity study was carried out on conventional mice weighing about 20grams.

The compounds corresponding to the general formula I according to thepresent invention and the pharmaceutically acceptable salts thereof wereadministered orally. The DL₅₀ was calculated according to the method byL. C. Miller and M. L. Tainter--Proc. Soc. Exper. Biol. Med., 1944,57,261. All of the administered compounds showed a very low toxicity andit will be particularly noted that the compounds of Examples 12 and 14have a LD₅₀ greater than 500 mg/kg.

(B) Pharmacology

The pain-killing activity was studied according to Siegmund--J. Pharm.Exptl. ther., 1957, 119,453.

The compounds according to the present invention were administeredorally 30 minutes before the injection of phenyl benzoquinone.

All of the administered compounds have an excellent pain-killingactivity. In particular, the compounds of Examples 12 and 14 have a DE₅₀respectively equal to 7 mg/kg and 5 mg/kg.

The anti-inflammatory properties were revealed in an oedema test byinjecting carragenine into a rat's foot according to the technique of C.Winter, E. Ribley and G. Nuss--Proc. Soc. Exper. Biol. Med., 1962, 111,544 547.

The products were administered orally in suspension in a Tween-watermixture 2 hours before the experiment. All the administered compoundshave a good anti-inflammatory activity. It will particularly be notedthat the compound of Example 14 has a DE₅₀ of 3 mg/kg.

For comparison purposes, the following Table shows the LD₅₀ and DE₅₀values which were combined with some of the best known anti-inflammatoryproducts.

    ______________________________________                                                                  DE.sub.50 (carragenine)                             Products  LD.sub.50 mg/kg p.o.                                                                          mg/kg p.o.                                          ______________________________________                                        Naproxen  400              5                                                  Ibuprofen 900             14                                                  Aspirin   1500            135                                                 Phenylbutanone                                                                          400             30                                                  Indometacine                                                                             20              4                                                  ______________________________________                                    

(C) Therapeutic uses

Bearing in mind the perfect tolerance of the compounds according to thepresent invention, and their pharmacological properties, they may beused in human or animal therapeutics in the treatment of obstinate painsof an inflammatory nature for which prolonged treatment is applicable.

The clinical results have proved to be satisfactory in cases ofinflammatory or degenerative rheumatism.

The pharmaceutical preparations containing these active principles maybe administered orally, parenterally or rectally. The quantity in adoseage unit is generally from 25 to 150 mg. These pharmaceuticalcompositions may also contain other pharmaceutically and therapeuticallyacceptable active principles.

Some examples of pharmaceutical preparations containing the activeprinciples used in the experiments are provided in the following in anillustrative, non-limiting manner.

(a) Tablets

2-(4-methylpiperazino-2-oxoethyl 2-(2'-chloro-4-biphenylyl)propionatehydrochloride: 50 mg

excipient: lactose

(b) Capsules

2-(4-phenylpiperidino)-2-oxoethyl 2-(2'-chloro-4-biphenyl)propionate: 25mg

(c) Adult suppositories

2-(4-phenylpiperidino)-2-oxoethyl 2-(2'-chloro-4-biphenylyl)propionate:50 mg

Meprobamate: 100 mg

Semi-synthetic glycerides, quantity sufficient for 1 suppository of 1 g

(d) Injectable solution

2-(4-methylpiperazino)-2-oxoethyl 2-(2'-chloro-4-biphenylyl)propionatehydrochloride: 10 mg

Water for injectable preparation: 2 ml.

We claim:
 1. A compound having the formula (I) ##STR25## wherein xrepresents a monovalent group selected from a hydrogen atom and ahalogen atom, R represents a monovalent group selected from a hydrogenatom or a straight or branched alkyl group having 1 to 4 carbon atoms,and R₁ represents a group selected from the following: ##STR26## whereinX₁ represents a monovalent group selected from a hydrogen atom, ahalogen atom and a CF₃ radical, and Y represents a monovalent groupselected from a straight or branched alkyl group having 1 to 4 carbonatoms, a phenyl group and such group substituted by a substituentselected from a halogen atom and a CF₃ radical, and the therapeuticallyacceptable salts thereof.
 2. Compounds corresponding to formula (I) ofclaim 1, and selected from the group consisting of:N-phenylparabiphenylacetoxyacetamide;N(metatrifluoromethylphenyl)parabiphenylacetoxyacetamide;4-methyl-1-parabiphenylacetoxyacetyl piperazine hydrochloride;4-phenyl-1-parabiphenylacetoxyacetyl piperidine;4-(metatrifluoromethylphenyl)-1-parabiphenylacetoxyacetyl piperazinehydrochloride; 4-phenyl-1-[(4-phenyl phenyl)acetoxyacetyl]piperazine;4-methyl-1-[(4-orthochlorophenyl phenyl)acetoxyacetyl]piperazinehydrochloride;4-phenyl-1-[4-(orthochlorophenyl)phenylacetoxyacetyl]piperazinehydrochloride;4-(metatrifluoromethylphenyl-1-[4-(orthochlorophenyl)phenylacetoxyacetyl]piperazinehydrochloride; 4-(methachlorophenyl)-1-[(4-orthochlorophenylphenyl)acetoxyacetyl]piperazine hydrochloride; [2-(4-phenyl1-piperazinyl)-2-oxo]ethyl 2-para biphenyl propionate;2-(4-methylpiperazino)-2-oxoethyl 2-(2'-chloro-4-biphenylyl)propionatehydrochloride; 2-(4-phenylpiperazino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate; 2-(4-phenylpiperidino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate; and 2-(2-aminopyridine(-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate oxalate.
 3. The compound of claim 1wherein R₁ is ##STR27##
 4. The compound of claim 1 wherein R₁ is##STR28##
 5. The compound of claim 1 wherein R₁ is ##STR29##
 6. Thecompound of claim 1 wherein R₁ is ##STR30##
 7. A compound according toclaim 1 which is 2-(4-methylpiperazino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate hydrochloride.
 8. A compoundaccording to claim 1 which is 2-(4-methylpiperazino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate.
 9. A compound according to claim 1which is 2-(4-phenylpiperidino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionate.
 10. A compound according to claim1 which is2-(4-phenylpiperidino)-2-oxoethyl2-(2'-chloro-4-biphenylyl)propionatehydrochloride.
 11. A method for treatment of obstinate pains and painfulinflammatory syndromes, in a subject selected from the group consistingof humans and animals, which comprises administration to said subject ofan effective amount of a compound having the formula (I) ##STR31##wherein X represents a monovalent group selected from a hydrogen atomand a halogen atom, R represents a monovalent group selected from ahydrogen atom or a straight or branched alkyl group having 1 to 4 carbonatoms, and R₁ represents a group selected from the following: ##STR32##wherein X₁ represents a monovalent group selected from a hydrogen atom,a halogen atom and a CF₃ radical, and Y represents a monovalent groupselected from a straight or branched alkyl group having 1 to 4 carbonatoms, a phenyl group and such group substituted by a substituentselected from a halogen atom and a CF₃ radical, and the therapeuticallyacceptable salts thereof.
 12. Pharmaceutical compositions containing, inan amount effective to relieve obstinate pains and painful inflammatorysyndromes, a compound corresponding to formula (I) of claim 1 as anactive principle and a pharmaceutically acceptable carrier.